Children infected with HIV, in contrast to infected adults, often have higher virus loads and progress to AIDS faster. It is widely accepted that destruction of CD4+ T cells is the primary cause of immunodeficiency in HIV-1 infected adults and children. Macrophages, important cell components of the innate immune system and link between innate and adaptive immunity, are also important targets of HIV/SIV infection. Here, we propose to demonstrate that, in addition to the CD4+ T cells, monocytes/macrophages are also heavily involved in the rapid progression to AIDS in HIV infected children. We have recently shown that the massive turnover of peripheral monocytes associated with death of tissue macrophages correlates with AIDS progression and is a better predictive marker for AIDS progression in adult macaques than CD4+ T cell decline. Our preliminary study also showed that in contrast to adult SIV infected monkeys, a very homogeneous high monocyte turnover was observed in all SIV-infected pediatric monkeys soon after infection. This turnover rate was equivalent to that observed in the adult infected monkeys in the terminal stages of AIDS. Our hypothesis is that massive early damage of tissue macrophages by SIV is the missing link that may explain the mechanism of rapid progression in pediatric AIDS.